2002 Fiscal Year Final Research Report Summary
Experimental study on blood-inner ear barrier function in MRP1 and p-glycoprotein gene knockout mice
| Project/Area Number |
13671776
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Otorhinolaryngology
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| Research Institution | Fukui Medical University |
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Principal Investigator |
SAITO Takehisa Fukui Medical University, Faculty of Medicine, Associate Professor, 医学部, 助教授 (10139769)
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| Co-Investigator(Kenkyū-buntansha) |
TSUZUKI Hideaki Fukui Medical University, University Hospital, Assistant Professor, 医学部附属病院, 講師 (90236927)
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| Project Period (FY) |
2001 – 2002
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| Keywords | p-glycoprotein / MRP1 / mdr1a gene knockout mouse / blood-inner ear barrier / RT-PCR / immunohistochemistry / pharmacokinetics / neurotoxic drugs |
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| Research Abstract |
The present study investigated the p-glycoprotein (p-gp) function in the inner ear using mdr1a p-gp gene knock-out mice [mdr1a(-/-) mice] and wild-type mdr1a(+/+) mice. Pharmacokinetic analyses indicated that mdr1a(-/-) mice displayed hypersensitivity to p-gp transported drugs such as doxorubicin (adriamycin) and vinblastine, and increased accumulation of these drugs in the inner ear compared with that in mdr1a(+/+) mice. However, increased accumulation was not detected after administering with ototoxic drug cisplatin, indicating that p-gp had a selectivity for extruding drugs. Electrophysiological studies using auditory brainstem response showed elevated thresholds and prolongations of wave I and wave I to V interpeak latencies only in mdr1a(-/-) mice after administering with doxorubicin or vinblastine alone. Furthermore, inhibition of p-gp function by co-administration with cyclosporin A in mdr1a(+/+) mice resulted in increased accumulation of doxorubicin and vinblastine in the inner
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ear. After pretreatment with cyclosporin A, hearing impairment was detected in mdr1a(+/+) mice treated with doxorubicin or vinblastine alone. From these results, it was suggested that mdr1a p-gp, which acts as an efflux pump, prevented ototoxicity induced by p-gp substrate drugs such as doxorubicin and vinblastine in wild-type mice.
Expression of multidrug resistance protein 1 (MRP1) was detected in the rat cochlea and in the vestibular labyrinth and endolymphatic sac of the guinea pig by immunohistochemical analyses. MRP1 was detected in the lateral wall of the stria vascularis, spiral ligament, spiral prominence and in the cochlear nerve fibers of the modiolus. Furthermore, MRP1 was found in the epithelial lining of the crista ampullaris, utricle, saccule, and epithelial cells of the endolymphatic sac. Since p-gp and MRP1 act as extrusion pumps, they may participate in a bipolar permeation barrier for selected drugs crossing the blood-inner ear barrier resulting in a low concentration of toxic substances and therapeutic drugs in the cochlea, vestibular organs and endolymphatic sac and play an important role in the blood-inner ear barrier. Less
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